Concerns resulting from the human anthrax cases in the Fall of 2001 have increased our need for a more complete understanding of the host response to Bacillus anthracis infection following aerosol exposure. The mechanism by which B. anthracis kills the host remains unknown, but mortality is high following aerosol exposure even when appropriate antibiotics are administered. This suggests that B. anthracis may be capable of evading or subverting one or more elements of the host response following infection. The innate immune system typically provides the first recognition of and defense against invading pathogens. Host innate immune cells have a repertoire of receptors for sensing, recognizing, and initiating responses to invading pathogens;these receptors include Toll-like receptors and intracellular NOD receptors. The overall goal of this project is to advance our understanding of the host innate immune response to B. anthracis. With a better understanding of the immune recognition pathways and host immune response, our future goal will be to identify immunomodulatory strategies to help prevent the rapid, sudden death typically observed in a host infected with B. anthracis. The specific goals of this proposal are to identify those host innate immune receptors that recognize B. anthracis spores and bacilli. In Specific Aim 1, we will determine the pathways and receptors activated by the interaction of the organism with the host using cell lines transfected with selected receptors. Preliminary results implicate Toll-like receptor 2 and MyD88-dependent pathways in this response. In Specific Aim 2, we will determine the contribution of the relevant innate immune receptors including Toll-like receptor 2 to protection of the host from inhalational anthrax infection using a mouse aerosol challenge model. A more complete understanding of the interaction of B. anthracis with the host will allow us to evaluate animal-based studies of B. anthracis vaccines and therapeutics, provide a foundation for the development of anthrax-directed immunotherapeutics, and provide important fundamental information applicable to a diverse group of bacterial pathogens. PUBLIC HEALTH RELEVANCE: Bacillus anthracis is the bacterial pathogen that causes anthrax. The inhaled form of anthrax typically results in sudden death of the host in spite of early recognition of the infection by healthcare workers and early use of antibiotics, as was seen with the anthrax cases in the Fall of 2001. The goal of this research is to determine how Bacillus anthracis interacts with the host's immune system in order to devise strategies for healthcare workers to help fight the infection.